A novel tumor-related biomarker, a HO-activatable photosensitizer 4 based on the 1,3-dicarbonyl enol moieties of hypocrellin B (3), was designed and synthesized. The photosensitizer 4 showed a blue-shifted absorption band compared with 3, and showed negligible photosensitizing ability without HO. However, the release of 3 from 4 by the reaction with HO regenerated the photosensitizing ability. Furthermore, 4 exhibited selective and effective photo-cytotoxicity against high HO-expressing cancer cells upon photo-irradiation with 660 nm light, which is inside the phototherapeutic window.